Epidemiology of cervical cancer by cell type.

A multicenter case-control study of 481 invasive cervical cancer patients and 801 population controls enabled comparison of risk factors for squamous cell tumors (n = 418), adenosquamous cancers (n = 23), and adenocarcinomas (n = 40). The epidemiology of the squamous cell tumors resembled that found in other studies, with the major risk factors being absence of Pap smear screening (relative risk = 3.6 to 4.8 for those not screened within 5 yr), multiple sexual partners (relative risk = 2.9 for over ten partners), and history of genital infections or sores (relative risk = 2.3). Although based on small numbers, adenosquamous tumors appeared to share some of these risk factors, notably number of sexual partners, years since last Pap smear, and level of education. Adenocarcinomas were not similarly affected, although sexual practices were marginally predictive. Obesity increased the risk of adenocarcinoma, but no other similarities to endometrial adenocarcinoma were observed. Smoking was a significant predictor of squamous cell tumors but did not affect adenocarcinomas. Extended use of oral contraceptives was a risk factor for all tumor types, especially adenocarcinoma, and a familial tendency to cervical cancer was also observed for all cell types.

Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV-infected women.

OBJECTIVE: To determine whether highly active retroviral therapy (HAART) is associated with better neurocognitive outcome over time among HIV-infected women with severely impaired immune function. METHODS: A semiannual neurocognitive examination on four tasks was administered: Color Trail Making, Controlled Oral Word Association, Grooved Pegboard and Four-Word Learning. This protocol was initiated in the HIV Epidemiological Research study (HERS) study when a woman's CD4 cell count fell to < 100 x 10(6) cells/l. Immune function (CD4), viral load status and depression severity (CESD) were also assessed semi-annually, along with an interview to determine medication intake and illicit drug use. RESULTS: HAART was not available to any participant at the time of enrollment (baseline), while 44% reported taking HAART at their most recent visit (mean duration of HAART 36.3 +/- 12.6 months). HAART-treated women had improved neurocognitive performance compared with those not treated with HAART. Women taking HAART for 18 months or more showed the strongest neurocognitive performance with improved verbal fluency, psychomotor and executive functions. These functions worsened among women not taking HAART. Substance abuse status, severity of depressive symptoms, age and educational level did not influence the HAART treatment effects on neurocognitive performance. Neurocognitive improvements were strongly associated with the magnitude of CD4 cell count increases. CONCLUSIONS: HAART appeared to produce beneficial effect on neurocognitive functioning in HIV-infected women with severely impaired immune systems. Benefits were greatest for women who reported receiving HAART for more than 18 months.

Discordant Human Immunodeficiency Virus Type 1 drug resistance mutations, including K103N, observed in cerebrospinal fluid and plasma.

Discordant resistance mutations were seen in human immunodeficiency virus type 1 (HIV-1) isolated from specimens of blood and cerebrospinal fluid (CSF) obtained from 3 of 6 patients. To our knowledge, this is the first report of HIV-1 isolated from CSF harboring the K103N mutation, which confers resistance to the nonnucleoside reverse-transcriptase inhibitors, and this finding may indicate that virus in the CSF replicates independently from virus in the blood compartment.

A longitudinal analysis of hospitalization and emergency department use among human immunodeficiency virus-infected women reporting protease inhibitor use.

The impact of protease inhibitors (PIs) on emergency department (i.e., emergency room [ER]) visits and hospitalizations was examined among a cohort of human immunodeficiency virus (HIV)-infected and high-risk women followed-up in the HIV Epidemiology Research Study (HERS) from 1993 through 1999. The rates of hospitalization and ER visits were measured as a function of recent or current PI use, age, race, transmission risk category, HERS site, baseline CD4 cell count, and baseline virus load; the PI effect was estimated separately by baseline CD4 cell count. In the HERS, PI use was strongly associated with lower rates of ER visits and hospitalizations for patients with baseline CD4 cell counts of <200 cells/mL (for hospitalizations: rate ratio [RR], 0.54; 95% confidence interval [CI], 0.33-0.89; for ER visits: RR, 0.38; 95% CI, 0.24-0.61). Other factors associated with increased hospitalization and ER use included history of injection drug use, low CD4 cell counts, and high virus loads.

Antiretroviral therapy in the year 2000.

The range of antiretroviral medications both in current use and in development is large, including five classes that do not overlap in their development of resistance. They are used in combinations generally including three or four drugs, and it is not feasible to test all possible combinations. Guidelines are available, however, thanks to the efforts of industry and academia to determine best treatment choices and alternatives. Considerations in the initial choice of antiretrovirals include likelihood of complete viral suppression, likelihood of adherence, development of side effects, and saving potent therapy for future therapy. Resistance testing, either phenotypic or genotypic or both, is useful in selecting subsequent regimens.

Use of cerebrospinal fluid shunt for the management of elevated intracranial pressure in a patient with active AIDS-related cryptococcal meningitis.

Persistently elevated intracranial pressure (ICP) is one of the most accurate predictors of a poor prognosis in patients with AIDS-related cryptococcal meningitis. We present a severe case of persistent cryptococcal meningitis in a patient with advanced AIDS, complicated by elevation of ICP. A ventriculoperitoneal shunt was placed that successfully lowered the ICP and alleviated the associated symptoms. The elevated ICP secondary to AIDS-related cryptococcal meningitis should be treated aggressively. Despite the risk of shunt complications, cerebrospinal fluid shunts can be considered in these patients if they do not respond to other treatment.

Internet sex-seeking leads to acute HIV infection: a report of two cases.

The use of the internet provides a rapid medium for identifying potential sexual partners and arranging in-person meetings that often result in sex. There is growing concern that the internet facilitates the transmission of sexually transmitted diseases and HIV. We report the first two cases of acute HIV infection after internet chat room encounters. Physicians should address the potential risks to sex seekers who use the internet. HIV prevention efforts that target internet sex seekers are needed.

A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral-naive patients: effect of sex and ethnicity.

OBJECTIVES: To compare the lipid and metabolic effects, efficacy, and safety of twice-daily regimens of Trizivir (abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg triple nucleoside tablet; TZV), Combivir (lamivudine 150 mg/zidovudine 300 mg combination tablet; COM)+nelfinavir (NFV), and stavudine (d4 T)+lamivudine (3TC)+NFV. STUDY DESIGN: An international, phase 4, open-label, parallel-group, 34-centre study was conducted in 254 non-diabetic, antiretroviral-naive, HIV-infected out-patients with an HIV-1 RNA level of >1000 HIV-1 RNA copies/mL and < or =200,000 copies/mL and a CD4 cell count of >50 cells/microL. METHODS: Patients were randomized 1 : 1 : 1 to TZV twice daily (n = 85), COM/NFV 1250 mg twice daily (n = 88), or d4T 40 mg+3TC 150 mg+NFV 1250 mg twice daily (n = 81) for 96 weeks. Treatments were compared using analysis of covariance (ANCOVA) with regard to changes from baseline in fasting lipids in the total population and in sex and ethnic subgroups. The proportions of patients achieving HIV-1 RNA <50 and <400 copies/mL were compared using a 95% confidence interval (CI) on the difference between proportions. RESULTS: The study population was diverse (50% female, 40% black and 37% Hispanic). Mean baseline low-density lipoprotein (LDL) cholesterol was 99 mg/dL, HIV-1 RNA was 4.43 log10 copies/mL and CD4 cell count was 355 cells/microL. At week 96, fasting LDL cholesterol changed minimally in the TZV group [least square mean (LSM) change from baseline, -8 mg/dL], but increased with d4T/3TC/NFV and COM/NFV (+29 and +19 mg/dL, respectively; P < 0.001 versus TZV). Week 96 LDL-cholesterol levels were significantly lower in the TZV group than in the other two treatment groups in women and men and lower than in the d4T/3TC/NFV group in Hispanic and black patients. In black patients, the week-96 LSM change from baseline in LDL cholesterol was significantly less with TZV than with d4T/3TC/NFV (+1 vs+39 mg/dL; P = 0.003). Total cholesterol >200 mg/dL occurred in a smaller proportion of patients receiving TZV (30%) compared with COM/NFV (50%) or d4T/3TC/NFV (60%; P = 0.005 vs TZV). High-density lipoprotein (HDL) cholesterol did not change markedly with any treatment. Although triglycerides increased, they changed least in women and Hispanic patients receiving TZV. Virological and CD4 responses to the treatments were similar in the total population and in the subgroups. Diarrhoea was reported more often in the NFV arms and nausea in the ZDV arms. CONCLUSIONS: Over 96 weeks, TZV twice daily has significantly less effect on LDL cholesterol than COM/NFV or d4T/3TC/NFV twice daily, especially in women and black patients, and is associated with similar virological and CD4 responses.

Relative importance of three iron-regulated outer membrane proteins for in vivo growth of Vibrio cholerae.

Iron is an essential nutrient to support the growth of most bacterial species. However, iron is not easily available to microorganisms infecting mammalian hosts, because it is largely sequestered by iron-binding proteins, such as transferrin or lactoferrin, or complexed to heme. In response to environmental iron stress, Vibrio cholerae produces the siderophore vibriobactin as well as a number of iron-induced outer membrane proteins. Previous data on the role of iron acquisition systems for the intraintestinal growth of mucosal pathogens such as V. cholerae are conflicting. In this report, we isolated mutants of V. cholerae with TnphoA fusions in each of viuA, hutA, and irgA, as well as strains mutant in each pair of these genes and all three simultaneously, to analyze the role of these iron-induced outer membrane protein receptors for in vivo growth of V. cholerae. The fusion between hutA and TnphoA in a single copy on the chromosome allowed the study of in vitro regulation of hutA in response to iron, fur, and irgB; transcription of hutA was tightly iron regulated (70-fold) and dependent on a functional Fur but did not require IrgB. To investigate the effects of mutations in these iron-induced outer membrane proteins on in vivo growth, we inoculated ileal loops in a rabbit model of infection. This avoids exposure of organisms to the potential killing effects of gastric acid, allows several logarithmic increases in growth in the in vivo environment, and facilitates direct comparison of multiple strains in the same animal to avoid any differences between animals. We grew each mutant to be tested in competition with the wild-type strain in the same loop, to provide an internal control. We confirmed that the inocula for these experiments were grown under conditions of iron stress prior to in vivo inoculation, by measuring the alkaline phosphatase activity of the iron-regulated fusion in each strain. The results confirmed that mutation of irgA produced a much more substantial in vivo growth defect than mutation of either hutA or viuA alone. Double mutants of irgA with either viuA or hutA, or the strain mutant in all three genes, showed an in vivo growth defect comparable to the strain mutant in irgA only, suggesting that mutation of irgA was the most relevant for in vivo growth. The strain mutant in both hutA and viuA was also markedly impaired for in vivo growth, suggesting that mutation of both of these iron uptake systems simultaneously can also produce a substantial in vivo growth defect.

Phase variation in tcpH modulates expression of the ToxR regulon in Vibrio cholerae.

We evaluated a spontaneous mutant of Vibrio cholerae, which was avirulent in an infant mouse and had reduced expression of cholera toxin and TcpA in response to environmental signals. The toxR, toxS and toxT genes in the mutant were normal, but transcription of toxT was absent. A plasmid expressing wild-type tcpP and tcpH complemented the mutant. The mutation resulted from a frameshift in a string of nine G residues within tcpH; similar slipped-strand mutations in tcpH arose at a frequency of 10(-4) during overnight growth and in the majority of colonies by the end of 5 days of growth in ToxR-inducing conditions. Transcription of tcpPH was regulated by temperature and pH independently of ToxR or ToxT. These results suggest that TcpH couples environmental signals (temperature and pH) to expression of the ToxR regulon, and provide a model for phase variation in the co-ordinate expression of cholera virulence factors.

Plateau in body habitus changes and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy: a 3.5-year study.

BACKGROUND: In a previously reported study, 21 women (propositi) who reported changes in body habitus during highly active antiretroviral therapy (HAART) were evaluated and compared with 21 women (comparison group) on HAART who did not report body habitus changes. Mean durations of HAART at baseline evaluation were 12.5 and 15.2 months for the propositi and comparison group, respectively. OBJECTIVE: Follow-up of the propositi and comparison group was conducted to determine whether body habitus changes and lipid abnormalities are progressive, stable, or improved with time and alteration of the HAART regimen. METHODS: Patients were evaluated by standardized interview, physical examination, body weight, body mass index, CD4 cell count, plasma HIV RNA levels, and lipid profiles. RESULTS: Fourteen of 21 propositi were available for follow-up. The mean duration of HAART was 42.7 months; body habitus changes were stable in 10 of the 14 women. Thirteen of 21 women in the comparison group were available for follow-up after a mean duration of HAART of 38.5 months; 2 of the 13 women had developed body habitus changes at follow-up. In both groups, mean serum lipid values at follow-up remained elevated to levels associated with increased cardiovascular risk. CONCLUSIONS: Body habitus changes in women most often developed within 1 year of initiation of HAART. Changes were largely stable after 2.5 additional years of HAART. Only modest and inconsistent improvement was achieved with alteration in the HAART regimen. Serum lipid abnormalities evident within the first year of HAART were also stable with 2.5 additional years of therapy.

Changes in body habitus and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy (HAART).

Twenty-one women (propositi) who expressed serious concerns about changes in body habitus during highly active antiretroviral therapy (HAART) were evaluated by thorough physical examination, anthropometric measurements, and serum lipid and endocrine assays. The same evaluations were carried out in a comparison group of 21 women who received HAART but did not complain of changes in habitus. No significant demographic differences were found between the propositi and the comparison group, nor were there significant differences in CD4 count or plasma viral load (PVL) between the two groups. Lipid analyses were also performed on plasma obtained prior to HAART from 12 of the women. The frequency of changes reported by the 21 propositi were increase in abdominal size (90%), increase in breast size (71%), weight gain of >5 kg (43%), peripheral fat wasting (43%), buttock fat wasting (38%) and development of cervicodorsal fat pad (19%). A subset of patients in the comparison group experienced increase in abdominal size (29%) and weight gain >5 kg (19%), but none experienced clinically detectable peripheral or buttock fat wasting, increased breast size, or development of cervicodorsal fat pads. Mean waist circumference, waist-to-hip ratios (WHR), body fat, and body mass index (BMI) were above the desirable range for women in both propositi and the comparison group. Levels of total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol associated with increased cardiovascular risk were found in 48%, 62%, 45%, and 33%. respectively, of the propositi, with similar findings in the comparison group. Fasting insulin levels were elevated in 4 propositi and 6 of the comparison group; mean insulin levels were within the normal range for both groups. In the comparison of lipids for the subset of patients before and after HAART therapy, HAART was associated with significant increases in total cholesterol, apolipoprotein B, and HDL cholesterol. Changes in body habitus caused by redistribution of fat occur commonly in women receiving HAART. Serum lipid abnormalities also are common during HAART and appear to be as frequent in women who do not experience clinically apparent body fat redistribution as in those who do. The observed changes in body fat distribution and in serum lipid levels are alterations that have been strongly correlated with increased risk for cardiovascular disease. Therefore, an understanding of the basis of these phenomena, and the risks with which they may be associated in this population, will be important for therapeutic decision making in women with HIV disease.

Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy.

Efavirenz, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, is a promising addition to the antiretroviral armamentarium. Efavirenz levels and HIV-1 RNA levels were measured in cerebrospinal fluid (CSF) and plasma of 10 HIV-1-infected patients taking efavirenz, 600 mg daily, in combination with other antiretroviral medications. Efavirenz was detected in the CSF at a mean concentration of 35.1 nM (range, 6. 6-58.9 nM), which was above the IC95 for wild-type HIV-1. The mean CSF-to-plasma ratio was 0.61% (range, 0.26%-0.99%). CSF HIV-1 RNA levels were ascertained in 9 of the patients; all were <400 copies/mL after a mean of 26 weeks on therapy. Eight of the 9 patients had no detectable virus in plasma. These results indicate that efavirenz is present in the CSF at low levels and is effective in suppressing CSF viral levels when used in combination therapy.

Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team.

BACKGROUND: Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). We compared two regimens containing efavirenz, one with a protease inhibitor and the other with two nucleoside reverse-transcriptase inhibitors, with a standard three-drug regimen. METHODS: The study subjects were 450 patients who had not previously been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. In this open-label study, patients were randomly assigned to one of three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg every eight hours). RESULTS: Suppression of plasma HIV-1 RNA to undetectable levels was achieved in more patients in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors than in the group given indinavir plus nucleoside reverse-transcriptase inhibitors (70 percent vs. 48 percent, P<0.001). The efficacy of the regimen of efavirenz plus indinavir was similar (53 percent) to that of the regimen of indinavir, zidovudine, and lamivudine. CD4 cell counts increased significantly with all combinations (range of increases, 180 to 201 cells per cubic millimeter). More patients discontinued treatment because of adverse events in the group given indinavir and two nucleoside reverse-transcriptase inhibitors than in the group given efavirenz and two nucleoside reverse-transcriptase inhibitors (43 percent vs. 27 percent, P=0.005). CONCLUSIONS: As antiretroviral therapy in HIV-1-infected adults, the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is better tolerated than the combination of indinavir, zidovudine, and lamivudine.